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Circulation. 2019 Jul 23;140(4):293-302. doi: 10.1161/CIRCULATIONAHA.118.039410. Epub 2019 Jun 3.

Development and Validation of a New Risk Prediction Score for Life-Threatening Ventricular Tachyarrhythmias in Laminopathies.

Author information

1
APHP, Cochin Hospital, Cardiology Department, FILNEMUS, Centre de Référence de Pathologie Neuromusculaire Nord/Est/Ile de France, Paris-Descartes, Sorbonne Paris Cité University (K.W., D.D.).
2
INSERM Unit 970, Paris Cardiovascular Research Centre (PARCC), France (K.W., C. Stalens, E.J.).
3
APHP, Centre de référence de pathologie neuromusculaire Paris-Est, FILNEMUS, Myology Institute, Neurology Department (R.B.Y., A.F., T.S., A.B., S.L.-L., K.C., H.-M.B., B.E.).
4
Sorbonne Universités, INSERM UMRS 974, CNRS, UMR-7215, Center for Research in Myology, Myology Institute,(R.B.Y., G.B.).
5
APHP, Institute of Cardiology (E.G., X.W., P.C.).
6
Sorbonne Universités, UPMC Univ Paris 06, INSERM 1166, Institute of Cardiometabolism and Nutrition (ICAN), France (E.G., P.C.).
7
Centre de Référence des Maladies Cardiaques Héréditaires, Paris, France† (E.G., P.C.).
8
Cardiology Department, University Hospital of Rouen, France (F.A.).
9
Inherited Cardiovascular Diseases Unit, University College London & St. Bartholomew's Hospital, United Kingdom† (T.G., K.S., P.E.).
10
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (N.K.L., U.B.T.).
11
Aix Marseille University, INSERM, GMGF; Department of Medical Genetics, Childrens' Hospital La Timone, France (A.D.S.-G., N.L.).
12
Medical Affairs Department, AFM-Telethon, Evry, France (C. Stalens).
13
Centre de reference des maladies rythmiques héréditaires, Bordeaux University Hospital (CHU), IHU Liryc, Electrophysiology and Heart Modeling Institute, fondation Bordeaux Université, Univ. Bordeaux, INSERM U1045, France (F.S.).
14
Université François Rabelais, Cardiology Department, CHU Tours, France (D. Babuty).
15
INSERM, UMR1087, Université de Nantes, L'Institut du Thorax, CHU de Nantes, CIC, Centre de référence pour la prise en charge des maladies rythmiques héréditaires de Nantes, France† (J.-N.T.).
16
Department of Electrophysiology and Pacing, InParys Clinical Research Group, Clinique Ambroise Paré, Neuilly-sur-Seine, France (G.M.).
17
William Harvey Research Institute, Queen Mary University London, United Kingdom (K.S.).
18
APHP, Hôtel-Dieu Hospital, Centre d'Epidémiologie Clinique, INSERM U1153, Université Paris Descartes - Sorbonne Paris Cité, France (R.P.).
19
APHP, Hôpital Raymond Poincaré, Centre de Référence des maladies neuromusculaires Nord-Est-Île de France, Garches (P.L., A.F.).
20
Hôpital Européen Georges Pompidou, Département de Cardiologie, Unité de Rythmologie, Paris, France (E.M.).
21
Centre de référence des maladies neuromusculaires AOC, Hôpital Pellegrin, CHU Bordeaux, France (G.S., X.F.).
22
Cardiology Department, University Hospital of Caen, France (F.L.).
23
APHP, UF Cardiogénétique et Myogénétique, Centre de Génétique, GH Pitié Salpêtrière, Paris, France (P.R., C.M.).
24
APHP, Centre de référence des maladies neuromusculaires Nord/Est/Ile de France, Service de Neurologie, Réanimation et Réeducation Pediatriques, Hôpital Raymond Poincaré, Garches, France; UMR 1179 INSERM, Université Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux (S.Q.-R., I. Dabaj).
25
Cardiologie A, University Hospital, Lille, France (D.K.).
26
CHU Lille, Endocrinology, Diabetology and Metabolism, Univ Lille, Inserm, UMR 1190 -Translational research in diabetes; EGID European Genomic Institute for Diabetes, France (M.-C.V.).
27
Service de Cardiologie, Hôpital Est, Lyon, France† (P.C.).
28
Department of Cardiology, La Timone Hospital, Aix-Marseille Université, France (P.A.).
29
APHM, Centre de référence des maladies neuromusculaires PACA-Réunion-Rhône Alpes, Hôpital Timone; Aix Marseille Université, Inserm UMR_S 910, GMGF, France (E.S.).
30
Department of Cardiology, Institut Lorrain du Coeur et des Vaisseaux, CHU Nancy-Brabois, Vandoeuvre les Nancy Cedex, France (N.S.).
31
Univ Rennes, CHU Rennes, Inserm, LTSI - UMR 1099, France (P. Mabo, R.M.).
32
Département de Rythmologie, Clinique Pasteur, Toulouse, France (N.C.).
33
University Hospital Rangueil, Cardiology department; Unité Inserm U1048, Toulouse, France (P. Maury).
34
Département de Cardiologie, Centre Hospitalier Universitaire de Nancy; INSERM-IADI U1254, Vandœuvre lès-Nancy, France (J.-M.S.).
35
Department of Cardiology, Division of Medicine (J.M.K., J.V.), The Royal Melbourne Hospital and University of Melbourne, Victoria, Australia.
36
Department of Cardiology, Leiden University Medical Centre, the Netherlands (A.G.A.A., K.Z.).
37
Department of Genetic Medicine (T.T.), The Royal Melbourne Hospital and University of Melbourne, Victoria, Australia.
38
AP-HP, Centre de référence des maladies neuromusculaires Nord/Est/Ile de France, service de neurologie pédiatrique, Hôpital Necker, GH Necker-Enfants malades, Paris, France (C.B., I. Desguerre).
39
Centre de référence des maladies neuromusculaires AOC, Département de Neurologie, Hôpital Purpan, CHU Toulouse, France (B.C.).
40
Service de Génétique Médicale, Hôpital Purpan, CHU Toulouse, France (E.B.).
41
AP-HP, Hôpitaux de l'Est Parisien, Cardiology Unit, Hôpital Saint-Antoine; Sorbonne Universités, INSERM, UMR_S 938, Paris, France (F.B.).
42
Hospices Civils de Lyon, Centre de référence des maladies neuromusculaires PACA-Réunion-Rhône Alpes, Service d'ENMG, Hôpital Neurologique Pierre Wertheimer, Lyon-Bron, France (F.B., P.P.).
43
AP-HP, Unité Médico-Chirurgicale de Cardiologie Congénitale et Pédiatrique, Centre de référence des Malformations Cardiaques Congénitales Complexes-M3C, Hôpital Necker Enfants Malades, Université Paris Descartes, Sorbonne Paris-Cité, France (D. Bonnet).
44
Hôpital privé Le Bois, Service de Cardiologie, Lille, France (S.B.).
45
Unité de Génétique Clinique, CHU Rouen, France (A.-C.B.).
46
Centre de Référence des maladies neuromusculaires Nord/Est/Ile de France, Service de neurologie, CHU Caen; INSERM U1075, Université de Normandie, Caen, France (F.C., S.S.).
47
Centre de Référence des maladies neuromusculaires Nord/Est/Ile de France, Service de Neuropédiatrie, Hôpital Roger Salengro, CHRU Lille (J.-M.C.).
48
Service de Cardiologie, CHU Montpellier, France (J.-M.D.).
49
Centre de Référence Maladies Rares CLAD-Ouest, Service de Génétique Clinique, CHU Rennes, Hôpital Sud, France (F.D., M.F.).
50
Unité de Génétique Clinique, Hôpital Couple Enfant, CHU Grenoble, INSERM U1216, Grenoble Institut des Neurosciences Cellular Myology and Pathologies, France (K.D.).
51
Centre de référence des maladies neuromusculaires AOC, Service de Neuropédiatrie, CHU Angers, France (J.D.).
52
Département de Neurologie, Hôpitaux Universitaires de Strasbourg, France (A.E.-L.).
53
Service de cardiologie, CHU Clermont-Ferrand; CNRS équipe thérapies guidées par l'image, Institut-Pascal, France (R.E.).
54
Basic and Translational Myology Laboratory, UMR8251, Université Paris Diderot/CNRS, France (A.F.).
55
Génétique médicale, CHU Estaing, Clermond-Ferrand, France (C.F.).
56
APHM, pole ENDO, Hôpital la conception; INSERM, INRA, C2VN, Aix Marseille University, France (B.G.).
57
Cardio-Thoracic Surgery Unit and Pathology Department, Rouen University Hospital, France (A.G.).
58
Department of Cardiology, Assistance Publique-Hôpitaux de Paris and INSERM U970, Hôpital Européen Georges Pompidou, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, France (A.H.).
59
Centre de Référence des maladies neuromusculaires Nord/Est/Ile de France, Service de neuropédiatrie, Hôpital Trousseau, Paris, France (A.I., M. Mayer).
60
APHP, Department of Genetics (I.J., O.L., C. Vatier, C. Vigouroux), Pitié-Salpêtrière University Hospital, Paris, France.
61
Sorbonne University, Inserm U938, Saint-Antoine Research Centre, Institute of Cardiometabolism and Nutrition, Paris, France (I.J., O.L., C. Vatier, C. Vigouroux).
62
APHP, Saint-Antoine University Hospital, Department of Molecular Biology and Genetics, Paris, France (I.J., O.L., C. Vatier, C. Vigouroux).
63
Centre de référence des maladies neuromusculaires AOC, Department of Neurology, CHU Montpellier, France (R.J.M.).
64
CHRU de Tours, Université François Rabelais de Tours, UMR INSERM U1253, Tours, FILNEMUS, French neuromuscular reference centers, France (E.L.).
65
Univ. Lille, Inserm U1167, Institut Pasteur; CHRU de Lille, Department of Cardiology, France (N.L.).
66
Centre de Référence des maladies neuromusculaires Nord/Est/Ile de France, Service de neuropédiatrie, CHU Strasbourg, Hôpital Hautepierre, Hôpitaux Universitaires de Strasbourg, France (V.L.).
67
InParys Clinical Research Group, Clinique Ambroise Paré, Neuilly sur Seine, France (A.L.).
68
Service de Génétique, Hopital Cochin, AP-HP, Paris (F.L.).
69
Centre de Référence des Maladies Neuromusculaires AOC, Laboratoire des Explorations Fonctionnelles, CHU de Nantes, France (A. Magot, Y.P.).

Abstract

BACKGROUND:

An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation.

METHODS:

We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator-treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range].

RESULTS:

We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0-7.2] and 5.1 [2.0-9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711-0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642-0.959), and the calibration slope was 1.082 (95% CI, 0.643-1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach.

CONCLUSIONS:

In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators.

CLINICAL TRIAL REGISTRATION:

URL: https://www.clinicaltrials.gov. Unique identifier: NCT03058185.

KEYWORDS:

death, sudden; defibrillators, implantable; tachycardia, ventricular

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